# NM_016284.5(CNOT1):c.3923G>A (p.Arg1308His)

https://sugi.bio/variant/cnot1-p-arg1308his

## Summary

**CNOT1 p.Arg1308His (c.3923G>A)** is classified **Uncertain significance** in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.128); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the CNOT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CNOT1](https://sugi.bio/atlas/gene/CNOT1/) |
| Protein change (HGVS p.) | p.Arg1308His |
| Coding change (HGVS c.) | c.3923G>A |
| MANE Select transcript | [NM_016284](https://www.ncbi.nlm.nih.gov/nuccore/NM_016284) |
| Variant type | single nucleotide variant |
| Location | chr16:58546404-58546404 (GRCh38) |
| ClinVar | [VCV4004346](https://www.ncbi.nlm.nih.gov/clinvar/variation/4004346/) |

**All HGVS expressions:** `NC_000016.10:g.58546404C>T`, `NC_000016.9:g.58580308C>T`, `NM_001265612.2:c.3908G>A`, `NM_016284.5:c.3923G>A`, `NM_206999.3:c.3923G>A`, `NR_049763.2:n.4181G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.128)
- REVEL 0.166 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.524 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.669, GERP 2.15, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.04** across the covering region of the MANE Select transcript (58,545,450–58,546,406), spanning 956 bp. Chi-square p 0.8. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000277% · 2/44,854 in the highest group · 6/1,461,742 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,427 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,504 |
| European (non-Finnish) | 0.000254% | 393,311 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CNOT1** population constraint: LOEUF 0.064, pLI 1, missense-Z 9.1629; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex neurodevelopmental disorder** — Definitive (AD)
- **holoprosencephaly 12 with or without pancreatic agenesis** — Limited (AD)

## Protein context {#protein}

Residue **1308** lies in an α-helix; a UniProt-annotated variant site (in vibos); the 'interaction with cnot6, cnot6l, cnot7 and cnot8' region.

AlphaFold model confidence (whole protein): pLDDT 75.22, 19% of residues very-high.

**21 experimental structure(s)** (PDB): [4C0D](https://www.rcsb.org/structure/4C0D), [4CQO](https://www.rcsb.org/structure/4CQO), [4CRU](https://www.rcsb.org/structure/4CRU), [4CRV](https://www.rcsb.org/structure/4CRV), [4CRW](https://www.rcsb.org/structure/4CRW), [4CT4](https://www.rcsb.org/structure/4CT4) — incl. mutant structure 5FU6.

## What this gene does {#gene-function}

*Describes the biological roles of CNOT1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CNOT1's established molecular role includes RNA binding. p.Arg1308His falls in the interaction with cnot6, cnot6l, cnot7 and cnot8 region.


### Pathways affected {#pathways}

CNOT1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Deadenylation of mRNA](https://reactome.org/content/detail/R-HSA-429947) | curated |
| [TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain](https://reactome.org/content/detail/R-HSA-6804115) | curated |
| [M-decay: degradation of maternal mRNAs by maternally stored factors](https://reactome.org/content/detail/R-HSA-9820841) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA binding, protein domain specific binding, nuclear estrogen receptor binding, nuclear retinoic acid receptor binding, molecular adaptor activity, armadillo repeat domain binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of cytoplasmic mRNA processing body assembly, negative regulation of translation, negative regulation of intracellular estrogen receptor signaling pathway, miRNA-mediated post-transcriptional gene silencing, negative regulation of retinoic acid receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-19.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-19 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CNOT1 variant pages (same residue, condition, or type): [CNOT1 p.Arg1308Cys](/variant/cnot1-p-arg1308cys), [CNOT1 p.Arg1308Gly](/variant/cnot1-p-arg1308gly), [CNOT1 c.5895+4T>C](/variant/cnot1-c-5895-plus-4t-c), [CNOT1 p.Ala1604Gly](/variant/cnot1-p-ala1604gly), [CNOT1 p.Arg211Cys](/variant/cnot1-p-arg211cys), [CNOT1 p.Arg369Cys](/variant/cnot1-p-arg369cys), [CNOT1 p.Asn1162Thr](/variant/cnot1-p-asn1162thr), [CNOT1 p.Asn1295Ser](/variant/cnot1-p-asn1295ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4004346). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*